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Angelina Jolie, BRCA Gene, Preventive Cancer Surgery

Angelina Jolie’s story in a New York Times Op Ed revealed the celebrity underwent not only a bilateral prophylactic mastectomy about two years ago, but also more recently, a bilateral oophorectomy (removal of the ovaries). (1)

In the Op Ed piece, Angelina Joli Pitt, wife of Brad Pitt, explained her decision to undergoing preventive surgery. She wanted to prevent the cancer that claimed her mother, grandmother and aunt. All died at young ages of breast/ovarian cancer. Genetic testing had disclosed Angellina was a BRCA gene mutation carrier. In her case the mutation was deleterious and carried a lifetime risk of breast/ovarian cancer in the 80-90 per cent range.(10)

Recent Studies Show Dramatic Reduction in Mortality

A recent large scale study by Dr. Finch in J Clin Oncologyshowed that prophylactic (preventive) mastectomy and oophorectomy (removal of ovaries) conferred a dramatic 70-80 percent reduction in mortality in BRCA gene women with familial breast/ovarian cancer.(6) This is quite impressive.(5-8)

I very much agree with this illuminating comment from Robert Pass, MD from New York:

Ms. Jolie Pitt is a remarkable individual who is to be applauded for sharing with the world her experiences. In doing so, she has almost certain saved more lives than any single physician may in a lifetime of practice. Thank you for your honesty and the education you have provided women everywhere. I admire you greatly for your courage and advocacy for women (and men). Thank you.” Quote Robert Pass, MD

Population Screening Proposed

The benefit of surgical treatment for women who carry deleterious BRCA Gene mutations is so impressive, some have advocated population wide screening “for unambiguously loss-of-function mutations with definitive effect on cancer risk.” (9)

Since mammography breast cancer screening has been disappointing, maybe this is not a bad idea. Would population screening for deleterious BRCA gene mutations lead to reduced mortality ? These studies have not yet been done, so we don’t know yet. Research on this is still in its infancy, and the gene testing technology is racing forward with testing costs cheaper every year.

Hormone Replacement after Surgically Induced Menopause

Angelina revealed in her op-ed that she was now taking hormone replacement for surgically induced menopause. Angelina mentions an estrogen patch. (This sounds like it could be the 17-Beta-Estradiol patch, Climara or Vivelle).

Angelina also revealed she uses a “progestin” impregnated IUD. (This sounds like the Mirena which has a synthetic chemically altered “progestin” levonorgestrel). I assume the Mirena IUD is to prevent endometrial hyperplasia and risk of endometrial cancer.

I would not recommend the Mirena IUD because it contains the synthetic progestin, levonorgestrel. Synthetic progestins such as levonorgestre cause adverse effects of migraine headache, acne and hair loss. There may be an association withbreast cancer, (for those who still have breast tissue). For more on adverse side effects of synthetic progestins, see my article on this topic.

Uterine Perforation by the IUD

Another adverse side effect of the Progestin impregnated IUD is perforation of the uterus. About 700 cases of per uterine perforation were reported in this report.

Some women dislike the Progestin impregnated IUDsbecause of adverse effects of unscheduled bleeding, abdominal pain, weight gain, mood disturbance, etc. Only half the women responded they were satisfied with this IUD.

Avoid the Mirena IUD

Instead of the Estradiol patch and Mirena IUD combination, I would recommend a more bioidentical approach. I would prescribe a topical cream containing both Estradiol and Estriol (called Bi-Est), as well as progesterone in the same cream. In addition, oral progesterone capsules at night before sleep are also given. We routinely do periodic hormone testing with either blood testing or 24 hour urinary metabolites. Annual pelvic sonograms are useful to measure endometrial thickness. Progesterone is FDA approved for prevention of endometrial hyperplasia and will maintain a thin endometrial lining. Any increase in endometrial thickness has further evaluation. see this link: FDA Approval of Progesterone Prevents Endometrial Hyperplasia. Left image Mirena IUD.

Declining Preventive Surgery and Avoiding “Self-Mutilation”

About 30-50% of BRCA carrier women decline the surgical procedures offered by mainstream medicine.(24) Reasons are unclear. However some women do not trust the medical system and wish to avoid ‘self-mutilation”. Others may have benign or clinically insignificant BRCA mutations which do not require heroic measures.

For ovarian cancer surveillance they have the CA-125 cancer marker test and pelvic and transvaginal sonogram . These types of surveillance programs have not proven to be reliable, as they may fail to detect ovarian cancer until after the cancer has spread throughout the peritoneal cavity, and to distant organs.

Alternatives to Preventive Surgery

The question remains: what alternatives can be offered BRCA gene carriers? The answer is the supplement, selenium, discussed in my book, Bioidentical Hormones 101, published four years ago. Since selenium is a mineral in our diet, and not a patented drug, it is rarely mentioned in the mainstream media accounts of Angelina Jolie and the BRCA Gene.(11-15)

The BRCA gene is involved in repairing oxidative damage to DNA using the seleno-protein repair system. The BRCA mutation carries the inability to repair double stranded DNA breaks. Increased markers of oxidative DNA damage can be measured in BRCA gene carriers. Selenium supplementation not only reduces the oxidative damage markers, it also reduces the incidence of breast cancer in the BRCA carrier to that of normal siblings. (11-15) Left image Brazil Nuts High in Selenium.

Selenium Beneficial for BRCA Gene Carriers – Reduces Breast Cancer

The most convincing evidence of selenium as a cancer preventive

Dziaman et al. from Poland published a study in Nov 2009 looking at DNA damage in BRCA gene carriers.(12) The authors measured serum and urinary products of DNA oxidation with and without selenium supplementation, finding damaged DNA products were higher in BRCA mutation carriers, and markers were reduced by selenium supplementation. Their results suggest that BRCA1 deficiency contributes to oxidative damage and breaks in cellular DNA, which may be responsible for cancer development. In addition, selenium supplementation is beneficial, because it protects the DNA from oxidative damage.

Strong Evidence for a Selenium as Preventive Agent – Kowalska

A study of BRCA gene carriers from Kowalska in Poland in 2005 provides strong evidence for selenium as a preventive agent.(13) Fifty five women with the BRCA1 gene mutation were supplemented with 275 µg of sodium selenite daily for 8 weeks. The amount of DNA damage was assessed from blood lymphocytes. This showed BRCA gene carriers had twice the DNA damage compared to their normal siblings. However, Selenium supplementation given to BRCA gene carriers reduced the DNA damage to normal levels, same as normal siblings. Left Image human lymphocyte courtesy of Wikimedia commons.

A second larger study reported by Kowalska et al, in 2006 verified that selenium supplementation indeed reduces cancer in women with the BRCA1 gene. After two years of selenium supplementation, expected BRCA1-associated cancers were reduced in half.(15)

Prudent for All BRCA Carriers to Take Selenium

Since selenium supplementation has no adverse effects, it would be prudent for all BRCA gene carriers to supplement with seleno-methionine (200-400 mcg/day).(11-14) We monitor serum selenium levels for safety.

We Need Long More Term Studies

We have yet to see studies examining the effect of selenium supplementation on mortality reduction in BRCA carriers. We simply do not know how selenium supplementation compares with preventive surgery offered by mainstream medicine, and this would be a fertile area for future study.

Cancer As a Metabolic Disease

In an article entitled, Cancer As a Metabolic Disease, we discuss a number of nutritional supplements available at the health food store which have strong anti-cancer activity. These include Resveratrol, Pterostilbene, Chinese Skullcap, Curcumin, Betulinic acid, Berberine, Artemesinin, Vitamin K2 , and Methyl Jasmonate. These types of natural substances induce apoptosis in cancer cells via the Hexokinase pathway. There are many others. A program including some of these supplements would be advisable for the BRCA gene carrier.

How can we explain the discrepancies and inconsistencies in BRCA Gene studies? I suggest this is explained by the hundreds of variations in the BRCA gene mutations. Only a few are deleterious leading to aggressive cancers with poor prognosis. Many of the BRCA variations are benign of no clinical significance.

Additional Testing Needed ?

In order to determine if the BRCA gene mutation is clinically significant, additional testing may prove useful to determine downstream functionality of the DNA repair mechanism disrupted by the BRCA mutation. One such test, the lymphocyte Bleomycin assay, was used by Dr. Kowalska in her study to measure functionality of the DNA repair mechanism before and after selenium supplementation.

In another study, Dr. Dzamian measured DNA products of oxidation in the blood and urine. He measured 8-oxodG levels in cellular DNA and urinary excretion of 8-oxodG and 8-oxo-7,8-dihydroguanine (8-oxoGua). These are markers of DNA oxidative damage indicating dysfunctional DNA repair mechanism. As yet, these are advanced tests for the research setting. Hopefully, similar tests for the clinical setting will be developed in the future.

Complexities and Pitfalls of Genetic Testing

This highlights the complexity and pitfalls of genetic screening for BRCA gene mutations. It would be unwise to undergo self testing with an online genetic testing service, which then yields a positive BRCA result, and then present oneself to a surgeon for preventive surgery. The BRCA mutation may be clinically insignificant, not requiring heroic measures. Evaluation by an expert genetic counselor is key here. This is a health professional who gathers all the pieces of the puzzle and puts them together. The genetic counselor considers the severity of the BRCA mutation, whether deleterious or benign, along with family history to hopefully arrive at a valid risk estimate and treatment recommendation.

You might be wondering why none of the BRCA gene studies include homozygous BRCA gene cases. All women are BRCA carriers indicating heterozygous state. Where are the homozygous BRCA gene cases ? Homozygous BRCA is lethal in the embryo, so we don’t have any.

Update 4/21/15 : Salivary BRCA Gene Kit for the Masses

“Color Genomics is offering a $249 saliva test kit for women that will check for 19 genetic variants known to be correlated with a higher risk of breast cancer or ovarian cancer, including mutations in the BRCA1 gene,” from Bloomberg Business.

Ms. Jolie Pitt is a remarkable individual who is to be applauded for sharing with the world her experiences. In doing so, she has almost certain saved more lives than any single physician may in a lifetime of practice. Thank you for your honesty and the education you have provided women everywhere. I admire you greatly for your courage and advocacy for women (and men). Thank you.

When a woman with this risky mutation has her ovaries and fallopian tubes removed, ideally by her late 30s to 40s, her lifetime risk of ovarian cancer can be slashed by as much as 80 percent, according to a large-scale study published last year in the Journal of Clinical Oncology.(Amy P.M. Finch,)

“We do not know whether Ms. Jolie is on an FDA-approved product, or an compounded one,” said Pauline M. Maki, president of the North American Menopause Society. “Given that she is using a patch, it is likely an FDA-approved form.” An earlier version of this story reported that compounded hormones do not require a prescription. This version of the story has been updated to report that they do.

6) http://jco.ascopubs.org/content/32/15/1547.full
Finch AP, Lubinski J, Møller P, et al. (2014) Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol 32:1547–1553.
The striking finding in this study of BRCA1 or BRCA2 mutation carriers was the effect of oophorectomy on all-cause mortality. Among women who were unaffected with cancer at study entry, risk of death in the follow-up period fell by 77% after oophorectomy. Impact of oophorectomy on mortality results in large part from reduction in the incidence of ovarian, tubal, and peritoneal cancers—but there is an important component from reducing breast cancer incidence and mortality as well. We have previously shown that oophorectomy reduces risk of breast cancer by 48% in women with a BRCA1 mutation,6 and once the cancer is diagnosed, it reduces patient case fatality by 70%.8
We confirm here the impact of oophorectomy on mortality in our study of 5,783 carriers, and we report that the effect of oophorectomy on all-cause mortality is equally strong for BRCA1 (HR, 0.30; 95% CI, 0.24 to 0.38) and BRCA2 mutation carriers (HR, 0.33; 95% CI, 0.22 to 0.50).
Women without a history of breast cancer may be administered hormone replacement therapy for the relief of the acute symptoms of menopause without increasing their risk of breast cancer. 14.?
Rebbeck TR, Friebel T, Wagner T, et al.(2005) Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: The PROSE study group. J Clin Oncol 23:7804–7810.
Eisen A, Lubinski J Gronwald J, et al.(2008) Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst 100:1361–1367.

2010

7) http://jama.jamanetwork.com/article.aspx?articleid=186510&quot;&gt;
Domchek, Susan M., et al. “Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.” Jama 304.9 (2010): 967-975.
Context Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer.
Objective To estimate risk and mortality reduction stratified by mutation and prior cancer status.
Design, Setting, and Participants Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009.
Main Outcomes Measures Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality.
Results No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer–specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer–specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]).
Conclusions Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality.

‘The authors showed 88% reduction in mortality from ovarian cancer in patents undergoing salpingo-oophorectomy in BRCA1 women, AND a 100% reduction in mortality with oophorectomy in BRCA2 women. (mortality was zero in this group)’

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If your goal is to reduce mortality from breast cancer , then throw away into the garbage can screening mammography, and instead screen the population for the BRCA gene…..offer surveillance or treatment options to these patients who are BRCA gene positive. …they decide what treatment they want …I guarantee you national annual breast cancer mortality will decline precipitously.

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We have other examples of familial cancer formers such as hereditary colonic polyposis. These people harbor numerous colonic polyps which transform into colon cancer. Colonoscopy is curative. It runs in families.

Yet the mortality reduction with surgical treatment of BRCA gene positive women is real and not to be ignored. Reduction in cancer mortality is tough to find in mainstream medicine. When we find something that give us a mortality reduction, we should say , “good job” and give some encouragement.

in BRCA gene women who have increased mortality from breast / ovarian cancer compared to their normal siblings, yes, prophylactic mastectomy and oophorectomy translates into reduced cancer mortality and reduced all-cause mortality. We have the data for that.

The Myriad patent on the BRCA test has been overturned by the court, so costs have come down as competitors offer the test.

Bilateral prophylactic salpingo-oophorectomy (BPSO) is used widely used to reduce the risk of breast and ovarian cancer in women with BRCA1 and BRCA2 mutations. However, the reduction in mortality after this surgery is unclear. We aimed to assess whether BPSO improves overall mortality or cancer-specific mortality in BRCA1 and BRCA2 mutation carriers.
Methods

We identified a prospective cohort of 666 women with disease-associated germline mutations in BRCA1 or BRCA2 and no previous cancer diagnosis. In our primary analysis, we compared 155 women who had had BPSO and 271 women matched for age at BPSO who had not had BPSO. In our secondary analysis, we compared 188 women who had had BPSO with 478 women who had not. In both analyses, we compared overall mortality and cancer-specific mortality. All analyses were adjusted for centre, mutation (BRCA1 vs BRCA2), and birth year.
Findings

In the primary analysis, mean follow-up from BPSO to censoring was 3·1 years [SD 2·4] in the BPSO group and 2·1 years [2·0] in the non-BPSO group. The hazard ratio (HR) for overall mortality was 0·24 (95% CI 0·08–0·71), for breast-cancer-specific mortality was 0·10 (0·02–0·71), and for ovarian-cancer-specific mortality was 0·05 (0·01–0·46) for women who had BPSO compared with those who had not. In secondary analysis, BPSO was associated with reduced overall mortality (HR 0·28 [95% CI 0·10–0·74]), but not with breast-cancer-specific mortality (0·15 [0·02–1·18] or ovarian-cancer-specific mortality (0·23 [0·02–1·87]. When regarded as a time-dependent covariate, BPSO was not associated significantly with mortality.
Interpretation

If confirmed, the finding that BPSO improves overall survival and cancer-specific survival in women with BRCA mutations will complement our existing knowledge of cancer-risk reduction associated with BPSO. Together, these data could give information to women who are considering genetic testing.

“Based on our 20 years’ experience working with families with cancer-predisposing mutations in BRCA1 and BRCA2,3 it is time to offer genetic screening of these genes to every woman, at about age 30, in the course of routine medical care. ”
Families were identified by recruiting more than 8000 healthy Ashkenazi Jewish men. Each male index participant was screened for 3 loss-of-function mutations that collectively account for the great majority of inherited cancer risk due to BRCA1 and BRCA2 in this population. BRCA1 and BRCA2 mutations are equally common in women and men and are inherited equally from mothers and from fathers. Men were tested as a gateway to families because men were unaffected by breast cancer themselves, thus enabling female mutation carriers to be identified only by relationship to a healthy male relative, not based on their personal or family history of cancer. By multiple criteria, the index men were representative of their population with respect to mutation prevalence and family history. For each of the 175 men identified as a carrier of a mutation in BRCA1 or BRCA2, genetic testing was offered to all female relatives.
In the United States as a whole, the number of carriers of actionable mutations in BRCA1 and BRCA2 carriers is estimated to be between 1 in 300 and 1 in 500 women,6 or between 250 000 and 415 000 adult women for whom breast and ovarian cancer is both highly likely and potentially preventable.

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10) http://www.sciencemag.org/content/302/5645/643.full
Breast and Ovarian Cancer Risks Due to Inherited Mutations in BRCA1 and BRCA2
Abstract Risks of breast and ovarian cancer were determined for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2. We selected 1008 index cases, regardless of family history of cancer, and carried out molecular analysis across entire families. The lifetime risk of breast cancer among female mutation carriers was 82%, similar to risks in families with many cases. Risks appear to be increasing with time: Breast cancer risk by age 50 among mutation carriers born before 1940 was 24%, but among those born after 1940 it was 67%. Lifetime risks of ovarian cancer were 54% for BRCA1 and 23% for BRCA2 mutation carriers. Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset…

Selenium is an important cofactor of various antioxidant enzymes and has been shown to enhance DNA repair in normal human fibroblasts. Oral selenium supplementation has also been shown to decrease the number of chromosome breaks in BRCA1 mutation carriers. Because the predisposition to cancer among BRCA1 mutation carriers may be linked to high rates of DNA damage and chromosome breakage, we evaluated the association between toenail selenium concentrations and three measures of DNA repair capacity (the single-cell alkaline gel electrophoresis (comet) assay, the micronucleus test, and the enumeration of gamma-H2AX nuclear foci) in female BRCA1 mutation carriers and in non-carriers.

Toenail selenium levels were inversely associated with levels of chromosomal damage following exposure to gamma-irradiation, as assessed by the micronucleus test. This association was limited to women with a BRCA1 mutation (p = 0.03). These results provide evidence for a possible protective effect of selenium against BRCA1-associated breast cancers.

Some experimental evidence suggests that BRCA1 plays a role in repair of oxidative DNA damage. Selenium has anticancer properties that are linked with protection against oxidative stress. To assess whether supplementation of BRCA1 mutation carriers with selenium have a beneficial effect concerning oxidative stress/DNA damage in the present double-blinded placebo control study. Altogether, these results suggest that BRCA1 deficiency contributes to (Oxidative Damage and Breaks ) accumulation in cellular DNA, which in turn may be a factor responsible for cancer development in women with mutations, and that the risk to developed breast cancer in BRCA1 mutation carriers may be reduced in selenium-supplemented patients who underwent adnexectomy.

Women who carry a mutation of the BRCA1 gene face a lifetime risk of breast cancer of ∼80% and a lifetime risk of ovarian cancer of ∼40% (1). Men who carry a BRCA1 mutation seem at elevated risk for breast and prostate cancer (2). The BRCA1 gene product is involved in the maintenance of the integrity of the human genome and functions in conjunction with BRCA2 and RAD51 to repair double-stranded DNA breaks through the mechanism of homologous recombination (3).

One of the most commonly used cytogenetic tests for the assessment of chromosome instability is the in vitro bleomycin assay (9). This is a simple and reproducible assay that measures induced chromosome breaks. Patient lymphocytes are cultured in the presence of bleomycin, a known mutagenic agent that typically induces double-strand breaks (similar to those induced by ionizing radiation). The mean number of chromosomal breaks per cell is then measured after bleomycin exposure. The assay has been used to study susceptibility to various types of cancer (9, 10). Using this technique, we explored the possibility that oral selenium supplementation may reduce the formation of induced chromosome breaks in female BRCA1 carriers.

An oral selenium solution was provided to the study subjects which contained 690 μg of pure selenium, in the form of sodium selenite (Na2SeO3) per mL of 70% ethanol. Subjects were requested to consume 0.2 mL of the solution twice daily. Among the BRCA1 carriers (n = 32), this level of supplementation resulted in an increase in the mean serum selenium from 56.7 ± 12.7 to 90.2 ± 17.6 ng/mL (P < 0.001). Selenium levels were not measured in the noncarrier controls.

In the first phase of this two-part study, we observed that the lymphocytes from heterozygous carriers of deleterious mutations of the BRCA1 gene show an elevated frequency of chromosome breaks after exposure to bleomycin in vitro compared with noncarriers. In the second part of the study, we have shown that in most cases, these elevated levels can be reduced to normal with oral selenium supplementation. Although our sample size was small, our results were highly significant; in every case, selenium supplementation resulted in a reduced frequency of chromosome breaks.

It has been shown that individuals with inherited predisposition to cancer (including colon, breast and ovary) have increased sensitivity to bleomycin. We published that bleomycin-induced chromosomal instability in BRCA1 carriers is inhibited by selenium supplementation in physiologic (according to WHO) doses.

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3 thoughts on “Angelina Jolie, BRCA Gene, Preventive Cancer Surgery”

The Risk for developing Cancer Depends on Type and location of the BRCA Mutation: Risk of Breast and Ovarian Cancer May Differ By Type of BRCA1, BRCA2 Mutation JAMA APRIL 7, 2015 Timothy R. Rebbeck, Ph.D